单核细胞在大多数炎症性疾病的发病机制中起着重要作用,包括自身免疫性疾病。在这里,不同的单核细胞亚群经常发挥差异,部分拮抗作用,在组织种群的调节中。类天疱疮疾病构成一组自身免疫性水疱性皮肤病,其特征是真皮明显渗入免疫细胞,包括单核细胞。单核细胞亚群浸润皮肤,然而,在很大程度上仍然难以捉摸。单核细胞粘附和募集到发炎组织受到趋化因子受体的调节,最突出的是CCR2和CX3CR1。为了描述单核细胞群体在自身免疫性起泡性皮肤病中的参与,我们使用多光子活体成像和趋化因子受体报告小鼠,时空监测浸润发炎皮肤的单核细胞群的动态光谱.通过将抗鼠VII型胶原蛋白(amCOLVII)IgG注射到Csf1rEGFP报告小鼠中来诱导实验性大疱性表皮松解症(EBA),循环的骨髓细胞,如单核细胞和中性粒细胞,表达一个EGFP。EGFP+细胞,包括中性粒细胞和单核细胞,存在于皮肤中,amCOLVII抗体在真皮-表皮交界处沉积后立即。进一步研究不同单核细胞来源的细胞群在疾病过程中的募集和参与,在CCR2RFP/+-报告基因和CX3CR1GFP/+-报告基因小鼠中诱导EBA。随着时间的推移,在患病小鼠及其各自的对照中发现了红色荧光蛋白(RFP)或绿色荧光蛋白(GFP)的可比分布。表明自身抗体结合后单核细胞向皮肤的相似募集。实验扩展到CCR2RFP/RFP缺陷型和CX3CR1GFP/GFP缺陷型小鼠,以确定在不存在受体的情况下单核细胞募集和疾病严重程度是否受损。在报告小鼠和缺陷小鼠中单核细胞募集到皮肤中都可以看到类似的模式。然而,与CX3CR1缺陷小鼠和报告小鼠之间相似的疾病严重程度相反,CCR2缺陷小鼠的疾病明显少于CCR2报告小鼠,如耳朵受影响面积的百分比所示。总的来说,我们的观察表明,虽然CCR2和CX3CR1受体不参与单核细胞向皮肤的募集,CCR2缺乏与小鼠实验性EBA疾病结局改善相关。
Monocytes play a significant role in the pathogenesis of most inflammatory diseases, including autoimmune diseases. Herein, different subpopulations of monocytes often play differential, partially antagonistic roles, in the regulation of tissue populations. Pemphigoid diseases constitute a group of autoimmune blistering skin diseases featuring a marked infiltration of the dermis with immune cells, including monocytes. The monocyte subsets infiltrating the skin, however, have largely remained elusive. Monocyte adhesion and recruitment into the inflamed tissues are regulated by chemokine receptors, most prominently by CCR2 and CX3CR1. To delineate the involvement of monocyte populations in autoimmune blistering skin diseases, we spatiotemporally monitored the dynamic spectrum of monocyte populations that infiltrate the inflamed skin using multiphoton intravital imaging and reporter mice for chemokine receptors. Experimental epidermolysis bullosa acquisita (EBA) was induced by injection of anti-murine type VII collagen (amCOLVII) IgG into the Csf1rEGFP-reporter mice, where circulating myeloid cells, such as monocytes and neutrophils, express an EGFP. EGFP+ cells, including neutrophils and monocytes, were present in the skin, immediately after the deposition of the amCOLVII antibody at the dermal-epidermal junction. To investigate the recruitment and involvement of different monocyte-derived cell populations in the disease course further, EBA was induced in CCR2RFP/+-reporter and CX3CR1GFP/+-reporter mice. A comparable distribution of red fluorescent protein (RFP)+ or green fluorescent protein (GFP)+ was found in both diseased mice and their respective controls over time, indicating the similar recruitment of monocytes into the skin following the binding of autoantibodies. Experiments were extended to the CCR2RFP/RFP-deficient and CX3CR1GFP/GFP-deficient mice to determine whether monocyte recruitment and disease severity are compromised in the absence of the receptor. A comparable pattern was seen in the recruitment of monocytes into the skin in both reporter and deficient mice. However, in contrast to similar disease severity between CX3CR1-deficient and reporter mice, CCR2-deficient mice developed significantly less disease than CCR2-reporter mice, as indicated by the percentage of affected area of ears. Collectively, our observations indicate that while CCR2 and CX3CR1 receptors are not involved in the recruitment of monocytes into the skin, CCR2 deficiency is associated with improved disease outcomes in experimental EBA in mice.